There were more than 48,000 organ transplants in the United States last year. They’re commonplace now, but the practice was considered experimental only a half-century ago.
Until just the past few years, transplants almost always involved human organs. Now, early experiments in xenotransplantation — transplanting animal organs into humans — are creating potential pathways to save lives.
Here’s a look back at how we got to this point.
Are animals the answer?
Xenotransplantation, the practice of transplanting organs between species, is a concept that has been around for hundreds of years.
Early in the 20th century, Dr. Mathieu Jaboulay turned the idea into action with one of the first well-documented attempts to make an animal organ work for a human. In 1906 in Lyon, France, Jaboulay attached a pig kidney to a 48-year-old woman’s elbow, choosing that spot because it was easy to access. Blood circulated through the kidney, and the kidney produced urine, something even some human donations in this period failed to do, studies show.
The pig kidney quickly failed, and the patient died soon after due to an infection.
“The lack of having ready access to human organs has always sort of been the holy grail, that you would have something in reserve that didn’t require a human to die in order for another human to live,” said Dr. Jeffrey Stern, a senior member of the NYU Langone Transplant Institute’s xenotransplantation team. “Obviously, animals as that source is sort of an ideal version of that.”
The first successful human transplant
In 1954, the world’s first successful human organ transplant was performed by Dr. Joseph E. Murray at what’s now called Brigham and Women’s Hospital in Boston.
Murray took a kidney from 22-year-old Ronald Herrick and transplanted it into Richard Herrick, his twin brother. Because they were identical, Richard’s immune system thought the new organ was its own, which prevented it from rejecting the foreign organ. Richard Herrick lived another eight years, and his organ donor brother had no harmful side effects.
“I think that really moved the field,” said Dr. Stefan Tullius, chief of the Division of Transplant Surgery at Brigham and Women’s Hospital.
“What that did show is that if you have the right combination and relationship between donor and recipient, then you indeed can transplant an organ and that is going to work,” Tullius added.
Since immunosuppressive drugs were not yet available, transplant experiments seemed to work only with twins whose immune systems thought the foreign organ were their own.
“You still ran into all those issues for the next 30 years with the immune system,” said Stern, who is also an assistant professor in the Department of Surgery at NYU Grossman School of Medicine. “Not everyone has an identical twin.”
More donors
In the 1960s, Murray demonstrated in several experiments with dogs that an organ transplant would be more successful if the recipient received drugs to suppress the immune system after the procedure, to lower the chances of rejection.
In April 1962, in a world first that built on what he learned from those experiments, Murphy transplanted a kidney from a deceased donor into an unrelated human who was treated with an immunosuppressant called azathioprine. The patient survived more than a year, and s survival time lengthened even further when doctors discovered that an immunosuppressant worked better if given along with the steroid prednisone.
In June 1963, one of Murray’s research fellows, Belgian surgeon Dr. Guy Alexandre, performed the first transplant operation from a brain-dead donor, a controversial procedure at the time. Alexandre had been searching for a kidney for a patient with renal failure when a woman who had been in a car accident was brought in to his Hôpital Saint-Pierre in Brussels. Her heart was beating, but she showed no brain activity. Knowing that organs lost viability as soon as a patient’s heart stopped, Alexandre got permission from his department chair to transplant the woman’s kidney into his patient with renal failure. The recipient lived another 87 days.
Over the next couple of years, Alexandre secretly performed other kidney transplants using brain-dead donors to see if such an approach would lengthen survival time compared with transplants from donors whose hearts had stopped. He disclosed the experiments at a medical conference a couple years later, to mixed reactions.
It wasn’t until 1968 that a Harvard Medical School committee published its recommendation that irreversible loss of brain function – once called “irreversible coma” – would be a new criterion for death. Afterward, transplants involving brain-dead donors became more common, vastly expanding the pool of available organs.
“To come up with the definition of brain death as an alternative to cardiac death – so the discontinuation of circulation – was huge, because it allowed the procurement of organs,” Tullius said.
Trial and error
Transplant doctors started experimenting with kidneys because humans have two and can survive with only one. Patients also had the option of dialysis if the transplant failed. But the more the doctors learned, the more confident they became that they could transplant other organs.
By the late 1960s, they started to experiment with livers and pancreases, and in 1967, South African surgeon Dr. Christiaan Barnard of Groote Schuur Hospital in Cape Town performed the first heart transplant. He transplanted a 25-year-old’s heart into a 53-year-old grocer who was dying from chronic heart disease. The grocer died 18 days later from a lung infection, but the heart continued to beat until his death.
Barnard’s second heart transplant patient lived almost 19 months. His fifth and sixth patients lived for almost 13 and 24 years, respectively.
By the 1990s, immunosuppressants like cyclosporine and tacrolimus opened new possibilities for transplants of multiple tissues. In 1998, Dr. Jean-Michel Dubernard did the first surgical hand transplant in Lyon, France. In 2005, he and Dr. Bernard Devauchelle performed the first partial face transplant for Isabelle Dinoire, a woman who lost part of her face in a dog attack. In 2010, a Spanish team led by Dr. Juan Barret performed the first full-face transplant.
“There’s the first 30 years of transplantation that everything was sort of experimental, right?” Stern said. “It wasn’t a commonplace endeavor that we do what we currently do, and it was a lot of trial and error and survival, and sort of the entire field of transplantation, I think, was very tenuous in that. It was adaptation and invention of new technologies that allowed transplantation to become commonplace.”
Baby Fae
In 1984, Dr. Leonard Bailey tried to save the life of Stephanie Fae Beauclair at Loma Linda University in California. The child, who became known as Baby Fae, was born with a deadly heart condition, and Bailey, who had been experimenting with cross-species transplants in animals, got permission to transplant a baboon heart. Stephanie lived just 21 more days, but the case generated more awareness about the need for infant organ donations and the possibility of cross-species transplantation.
Eventually, scientists decided that primates, although evolutionarily the closest cousin to humans, weren’t the best organ donors.
“Primates turned out to be too small, too expensive and too controversial,” said medical ethicist Dr. Art Caplan, who works with transplant cases at NYU. There was also a concern about infection. Non-human primates may carry a variety of pathogens that are not harmful to them but that can cause disease in humans, including Marburg virus and HIV.
Eventually, scientists realized that pigs would be a better option: They’re anatomically similar to humans, they breed quickly, and there was a reduced risk of zoonotic disease.
Nobel-winning technology
Research in xenotransplantation stalled until the development of the gene editing tool CRISPR in the early 2000s. This Nobel-winning technology gave scientists the ability to edit the pig genome to make it more compatible with humans’, including knocking out key sequences in pig DNA that would result in almost automatic organ rejection in people. Combining that with cloning techniques gave scientists a chance to maintain consistent genetics and produce universal pig donors.
“Cloning and to apply CRISPR, to have the opportunity of gene editing, is really allowing not only transplantation but is also relevant for other areas of medicine,” Tullius said. “I would put those in the revolutionary category.”
One step closer
Pig organs had been transplanted into non-human primates, but the real test came in September 2021, when a genetically engineered pig kidney was transplanted to a brain-dead patient at NYU Langone.
The kidney was attached to the blood vessels in the recipient’s upper leg, outside the abdomen, for 54 hours while doctors studied how well it functioned. The organ seemed to function as well as a human kidney transplant, and the doctors did not see any signs of rejection.
“The family graciously approved donation of their loved one’s body for this procedure. That extraordinary generosity paved the way for this major step forward in creating a sustainable supply of life-saving organs and hopefully ending the current paradigm that someone has to die for someone to live,” Montgomery said in a news release at the time.
Making history
On January 7, 2022, surgeons at the University of Maryland School of Medicine performed the first xenotransplant into a living person.
David Bennett, 57, could not walk and relied on an artificial lung and heart bypass machine to stay alive. He was too sick to qualify for a human heart but was able to undergo the experimental procedure under the US Food and Drug Administration’s compassionate use pathway, which allows patients with no other alternatives to try experimental treatments.
He lived two additional months, having the chance to spend more time with his family and watch the Super Bowl.
“As with any first-in-the-world transplant surgery, this one led to valuable insights that will hopefully inform transplant surgeons to improve outcomes and potentially provide lifesaving benefits to future patients,” said his surgeon, Dr. Bartley Griffith.
Bennett was the first of a handful of compassionate use xenotransplant patients. But as researchers approach clinical trials, they hope they will have a better understanding of how successful the organs can be under more typical circumstances.
“The promise of xenotransplantation is the promise of hope for our patients. A hope for the future that for too long has been uncertain. It is hope turned to possibility turned to reality. Our patients can dream again about graduations, weddings … about life. Hope should not have to be rationed,” said Dr. Jayme Locke, a professor of surgery at NYU Langone.
Custom organs
“Multiple shots on goal” is how geneticist Dr. David Ayares describes United Therapeutics’ approach to the future of organ transplantation.
This summer, the company will embark on the first FDA clinical trial of xenotransplantation.
“So instead of one-off compassionate use transplants that were very valuable in learning how to optimize and extend the survival of these patients, now we can go into a multicenter trial,” Ayares, president and chief scientific officer of Revivicor, a United Therapeutics subsidiary, told Gupta.
But that still won’t be enough to solve the organ shortage completely, so United Therapeutics and others in the transplant community are continuing to think farther into the future. “I think the next thing we’re going to do is … create personalized organs where we don’t have to use any immunosuppression,” Montgomery said of what he expects down the road.
This could mean using a pig’s organ as scaffolding where scientists could seed human stem cells, or even 3D-printing organs.
“Then you have a designer organ for that person when they need it,” Montgomery said.